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Tomorrow's Treatments Today

Humans have been practicing the healing arts at least since the days when papyrus scrolls contained the totality of our medical knowledge. Cancer was commonly thought to be caused by a bodily imbalance — an excess in black bile, if the ancient Greeks were to be believed, or an imbalance in qi, according to traditional Chinese medicine. While most ancient physicians considered cancer to be incurable, throughout history we have attempted to treat it with a range of interventions, from herbal medicines and oils, to arsenic and other harsh chemicals, to bloodletting and surgery. Unfortunately, for most of human history, cancer was a death sentence.

Today, both our understanding of cancer and our treatments for it have improved by leaps and bounds, feeding scientists’ optimism. That optimism has kept researchers busy, from the laboratory to patients’ bedsides. Initial investigation into new cancer treatments takes place far away from human subjects, with tests conducted in petri dishes and lab mice. But when one of these new agents shows promise in the laboratory, it’s time to test it in humans. These studies, called clinical trials, are the gold standard for figuring out which treatments are themost effective and the least harmful. The University of Arizona Cancer Center is Southern Arizona’s premier institution for clinical trials of new cancer drugs, and currently is conducting about 200 investigations into treatments for a variety of cancer types.

Clinical trials proceed in stages, starting in small sets of patients and expanding to larger groups as research objectives are met. Phase I clinical trials are the earliest investigations into a promising new drug. These “first-in-human” studies figure out if a treatment is safe and what dosage to administer. Subjects usually start out at low doses of the experimental drug; this dosage is slowly increased so researchers can see when side effects start to emerge. With a lot of work and a little bit of luck, they will find a drug that can be given at a dose high enough to show promise, but low enough not to cause intolerable side effects. These trials might also give early hints of a drug’s potential to fight cancer.

Our Phase I Program: Bringing Cutting-Edge Treatments to Arizona

Since its inception, the UA Cancer Center has participated in phase I trials, but these offerings were formalized when former UA Cancer Center director Daniel Von Hoff, MD, created a structured Phase I Program. Under Dr. Von Hoff’s mentorship, Daruka Mahadevan, MD, PhD, took over as director from 2007 through 2012. After a stint in Memphis, where he was director of the phase I program at the University of Tennessee’s West Clinic, Dr. Mahadevan was recruited back to the UA Cancer Center in January 2016 to direct the Phase I Program here. Since then, the program has steadily expanded.

Ruth Cañamar, the Phase I Program manager, speaks to this growth: “In a year and a half since the arrival of Dr. Mahadevan, we opened enrollment to 12 trials, doubled the size of our team and have enrolled 35 patients.”

The UA Cancer Center can’t do clinical trials without committed researchers and committed patients who participate in trials to help us understand new drugs. Researchers benefit from clinical trials when they learn more about how a new drug works in an actual living human — rather than in a test tube or lab animal. Patients benefit by gaining access to innovative investigational treatments, the costs of which generally are covered by pharmaceutical companies and a patient’s health insurance provider. Further down the line, future patients benefit when these trials culminate in the approval of safer, more effective cancer therapies, especially for cancers for which no other treatment options exist.

The swift advances made by basic science in recent years have driven the strides made in cancer treatment. Researchers in fields as diverse as translational medicine, cancer biology and imaging have built such a strong foundation for phase I trials that some of these new drugs have received accelerated FDA approval after showing positive results in those trials.

“The rule of thumb from a long time ago was 1 in 15 trials would pan out in phase I,” says Hani Babiker, MD, associate director of the Phase I Program. “Now we’re seeing more than 30 percent over the last two years or three years. It’s a really exciting field.”

With the increasing success of phase I trials in recent years, they are quickly shaking their reputation as a last resort in a cancer patient’s journey through available treatments.

“Phase I [studies] aren’t the same as they were just a few years ago,” says Ms. Cañamar, speaking to the taboo that, until recently, clung to phase I trials. “They’re clinical trials with real benefit to a patient. The reputation has changed, so they’re not the scary phase of a trial to get treatment on.”

Building Bridges

The UA Cancer Center’s involvement with phase I trials helps us build relationships with pharmaceutical companies, both big and small. For example, the UA Cancer Center has been designated as a preferred site by Bristol-Myers Squibb, which means we can work with the pharmaceutical giant from preclinical studies all the way through clinical trials.

“We are first in line to get their trials. They trust that we’re going to run the trial well,” Ms. Cañamar tells us, adding that our preferred site status also opens doors for UA Cancer Center scientists doing preclinical research. “Basic scientists don’t normally have that opportunity to work with big pharma, because usually these companies already have their own built-in labs, but they do want to work with academic health centers.”

The Phase I Program doesn’t just allow the UA Cancer Center to build relationships with big players in the pharmaceutical industry; it also allows us to make inroads into the community. Drs. Babiker and Mahadevan regularly meet with Tucson oncologists to make them aware of phase I studies available at the UA Cancer Center, increasing the referrals we get from the community. Often, there can be tension between the UA Cancer Center and other community oncologists, who fear we might be trying to retain their patients, but they are put at ease when they learn they will be kept apprised of their patients’ progress on a trial, and that their patients will return to them for care once a trial is over.

“We really are building a bridge with the community,” says Ms. Cañamar. “We have great trials and drugs that you can’t get in the community.”

Better Care, More Hope

Phase I studies also can offer an additional layer of care to an embattled cancer patient who has already been through standard therapies, but whose cancer continues to progress. These patients may be deeply fatigued by the often physically taxing, emotionally draining experience of cancer treatment, and might suffer from malnutrition, depression, compromised immune systems and organs on the verge of malfunction. UA Cancer Center researchers make sure these patients have access to nutritionists, physical therapists and social workers, all of whom can help them be at their best, giving them an edge as their bodies respond to experimental treatments.

All participants in phase I trials receive full genetic testing of their tumors, with specimens being sent to a central repository, or “biobank,” where they will help future scientists expand their understanding of cancer. Furthermore, receiving a full genetic profile of their cancer allows patients to be matched to a study targeted to their tumor type — a helpful opportunity for a patient, especially as our concept of cancer transitions from being a disease of an organ system to a disease of genetic mutations and aberrations.

Participation in these trials also can offer a source of hope to patients who have exhausted standard treatment options. Dr. Babiker mentions a patient whose cancer continued to grow even after he had completed two chemotherapy regimens. The toll the drugs had taken on his body was too high, and, with no more fight left, he resigned himself to spending his last days in hospice. A new drug, however, provided fresh optimism, and the patient decided to give treatment one last shot — and he responded to the experimental drug, experiencing a 73-percent reduction in his tumor.

“Right now, he’s active and he’s out of hospice,” reports Dr. Babiker, adding that being able to give hope to patients who thought they had run out of options is the most rewarding aspect of his work, especially when these treatments not only extend patients’ survival, but also enhance their quality of life.

“It’s like a snowball,” Dr. Babiker says. “You know if you help that patient, a lot of other patients are going to get better. That tops it all!”

Immunotherapy: The Fourth Modality

Unfortunately, despite the success stories, on the whole, cancer treatments are notorious for causing terrible side effects — you’ve probably heard patients lament that “the cure is worse than the disease.” While standard cancer treatments like chemotherapy and radiation attack cancer cells, they also can harm normal cells, which can make for an often punishing treatment regimen. Cancer doctors and their patients dream of a “magic bullet” — a drug that takes out tumors with sniper-like precision, leaving healthy cells alone.

Many experimental treatments fall outside the scope of surgery, radiation and chemotherapy. For example, immunotherapy is an emerging type of cancer treatment that can train the immune system to recognize and attack cancer cells. In fact, it was an experimental immunotherapy drug that gave Dr. Babiker’s formerly hospice-bound patient a new lease on life.

Julie Bauman, MD, MPH, the division chief of hematology and oncology at the UA College of Medicine – Tucson Department of Medicine, calls immunotherapy “the fourth modality,” after surgery, radiation and chemotherapy. While chemotherapeutic drugs have direct toxic effects on cancer cells, “immunotherapy doesn’t touch the cancer cell, per se,” Dr. Bauman explains. “Instead, it reactivates immune cells in your system to fight the cancer. When it works, the patient has a living army battling the cancer every day.”

UA Cancer Center is participating in the phase I trial for one such immunotherapy drug candidate. Promising preliminary results were reported at June’s American Society of Clinical Oncology meeting, showing that the drug was effective against locally advanced and metastatic cutaneous squamous cell carcinoma, a type of cancer that doesn’t have a standard treatment option. Overall, 12 of 23 patients — 52 percent — saw their tumors shrink, including two patients whose locally advanced cancers went into complete remission. As the study continues, researchers will learn more about this drug’s safety and effectiveness, but these positive early results are not lost on researchers.

“An overall response rate of more than 50 percent in a rare tumor that’s stage IV, that we don’t have any other options to treat with, is really huge,” says Dr. Babiker, who is leading this trial at UA Cancer Center.

“The most exciting trials I’ve done are those where we bring novel immunotherapies to patients with advanced head and neck cancer,” Dr. Bauman says. She has contributed to clinical trials that paved the way for the recent FDA approval of pembrolizumab (Keytruda®) and nivolumab (Opdivo®), two immunotherapies that are showing great promise in certain patient populations. Pembrolizumab gained some prominence when it was revealed to be the drug that helped put former President Jimmy Carter’s melanoma in remission — some media sources even referred to it as the “Jimmy Carter drug.”

For all of its promise, immunotherapy poses challenges. While it has a reputation for being less toxic than chemotherapy, it still carries the risk of autoimmune side effects — reactions that can happen when the immune system becomes too vigilant, attacking healthy cells in addition to cancer cells.

“Sometimes we ‘over-rev’ the immune system and we get autoimmune side effects,” Dr. Bauman says. “Those can be just as dangerous as immune-suppressive chemotherapy. We have to learn how to use immunotherapy, but we also have to learn how to make it more specific to cancer, so the immune system is educated to fight the cancer but not the patient.”

Not all cancers are susceptible to immunotherapy drugs — but researchers are hard at work finding drugs that will break down tumor cells’ defenses, making them more vulnerable to attack from the immune system and clearing the way for immunotherapy to do its job.

“Some tumor types are immunologically ʻcold,ʼ ” Dr. Mahadevan tells us, referring to cancers that fail to respond to immunotherapy. “In order to make them ʻhot,ʼ investigations are ongoing with novel combinations.” These drug combinations can deliver an efficient one-two punch to tumors that formerly were resistant to immunotherapy.

For example, oncolytic viruses, which are genetically engineered to target cancer cells, are under investigation at the UA Cancer Center. Dr. Mahadevan is overseeing research into the combination of an oncolytic virus with an immunotherapy drug. The lab-created virus infects tumors while ignoring healthy cells. Before succumbing to the lethal effects of the virus, the cancer cell is hijacked to produce more anti-cancer viruses, which go on to infect more tumor cells — a viral infection that actually works to the patient’s advantage.

Tumor cells killed by this virus also send signals to the immune system, triggering it to mount a targeted defense. This viral attack sets the stage for the immunotherapy drug, which attaches to the surfaces of immune cells and mounts a robust immune response. Researchers hope these two treatments, in tandem, can shrink tumors even more efficiently than they could by themselves.

Phase I Trials Give UA Cancer Center an Edge

These types of trials make the UA Cancer Center competitive, not only in Tucson, but nationwide. The study investigating the oncolytic virus, for example, is only open in a handful of cancer centers in the United States — not just here at the UA Cancer Center, but also at locations in California, Indiana and Michigan, giving us the ability to draw patients from across the region.

Another factor in keeping the UA Cancer Center competitive with other cancer centers is our ability to keep up with the fast pace at which phase I trials are conducted. The UA Cancer Center needs to be able to open trials quickly, which requires a small army of people across multiple departments working behind the scenes to put together paperwork for the U.S. Food and Drug Administration, institutional review boards and patients, and to negotiate budgets and contracts between the university and pharmaceutical companies. And, thanks tocertification from the Western Institutional Review Board, the UA Cancer Center receives expedited reviews of most industry trials, which gives us an edge.

“It’s a selling point for us,” says Ms. Cañamar. “We can really push to open our trials quickly. As an academic institution, we’re pretty competitive and are often complimented by sponsors at how quickly we have opened and completed their trials.”

The Phase I Program is an invaluable resource to cancer patients, who are able to become among the first to receive pioneering treatments that would not be available anywhere else.

“The goal of our Phase I Program is to provide an outstanding and compassionate service to our cancer patients with cutting-edge investigational agents,” Dr. Mahadevan says. “We are here to care for every single cancer patient who needs our help.”

From the herbal remedies and bloodletting of yesterday, to the immunotherapy and cancer-killing viruses of tomorrow, medical knowledge has expanded in ways our ancestors never could have dreamed of. If research continues apace, perhaps the next generation of patients will be benefiting from treatments that we are only beginning to imagine. To transform those dreams into reality, we need our Phase I Program to be as robust as possible, so it can contribute to the rapid accumulation of scientific knowledge — and deliver the medicine of the future to our patients today.